The present invention is in the field of enzyme proteins that are related to the sulfatase enzyme subfamily, recombinant DNA molecules, and protein production. The present invention specifically provides novel peptides and proteins that effect protein phosphorylation and nucleic acid molecules encoding such peptide and protein molecules, all of which are useful in the development of human therapeutics and diagnostic compositions and methods.
Many human enzymes serve as targets for the action of pharmaceutically active compounds. Several classes of human enzymes that serve as such targets include helicase, steroid esterase and sulfatase, convertase, synthase, dehydrogenase, monoxygenase, transferase, kinase, glutanase, decarboxylase, isomerase and reductase. It is therefore important in developing new pharmaceutical compounds to identify target enzyme proteins that can be put into high-throughput screening formats. The present invention advances the state of the art by providing novel human drug target enzymes related to the sulfatase subfamily.
Sulfatases
The novel human protein, and encoding gene, provided by the present invention is related to the sulfatase family of enzymes, including estrone sulfatases. Specifically, the novel human protein of the present invention is a novel alternative splice form of a gene provided in Genbank gi5689491 and published PCT patent application WO200055629 (see the BLAST and Genewise alignments of the sequences of the present invention and the sequences of gi5689491 and WO200055629 provided in FIG. 2). The evidence supporting alternative splicing includes a different polyA signal used to create the protein of the present invention compared with the art-known protein; the stop codon at cDNA positions 1223-1225 and polyA signal at cDNA positions 1750-1756 are present in the genomic sequence; and the last exon of the cDNA of the present invention crosses the splicing site of the corresponding exon 5 of the art-known protein (these differences are illustrated in FIG. 2 in the BLAST and Genewise alignments of the sequences of the present invention and the sequences of gi5689491 and WO200055629).
Novel human sulfatases, such as the protein provided by present invention, are particularly useful as targets for treating cancer, particularly breast cancer. Sulfatases are important for generating estrone and 5-androstenediol from sulfated precursors. As stated by Purohit et al., (Mol Cell Endocrinol 2001 Jan 22;171(1-2):129-135), xe2x80x9cThe development of inhibitors to block the formation of estrone and 5-androstenediol from sulfated precursors is an important new strategy for the treatment of breast cancerxe2x80x9d. Thus, sulfatase inhibitors are useful for treating cancer and, consequently, novel sulfatase proteins are valuable as novel targets for the development of anti-cancer therapeutic agents. Purohit et al. found that non-steroidal and steroidal sulfamates, particularly a tricyclic coumarin sulfamate (xe2x80x9c667 COUMATExe2x80x9d) and 2-methoxyestrone-3-O-sulfamate (2-MeOEMATE), inhibited estrone sulfatase activity and xe2x80x9coffer considerable potential for development for cancer therapyxe2x80x9d. The importance of sulfatases relating in breast cancer is further described in published PCT patent application WO200055629, xe2x80x9cNovel Methods of Diagnosing and Treating Breast Cancer, Compositions, and Methods of Screening for Breast Cancer Modulatorsxe2x80x9d.
Enzyme proteins, particularly members of the sulfatase enzyme subfamily, are a major target for drug action and development. Accordingly, it is valuable to the field of pharmaceutical development to identify and characterize previously unknown members of this subfamily of enzyme proteins. The present invention advances the state of the art by providing previously unidentified human enzyme proteins, and the polynucleotides encoding them, that have homology to members of the sulfatase enzyme subfamily. These novel compositions are useful in the diagnosis, prevention and treatment of biological processes associated with human diseases.
The present invention is based in part on the identification of amino acid sequences of human enzyme peptides and proteins that are related to the sulfatase enzyme subfamily, as well as allelic variants and other mammalian orthologs thereof. These unique peptide sequences, and nucleic acid sequences that encode these peptides, can be used as models for the development of human therapeutic targets, aid in the identification of therapeutic proteins, and serve as targets for the development of human therapeutic agents that modulate enzyme activity in cells and tissues that express the enzyme. Experimental data as provided in FIG. 1 indicates expression in humans in pancreas adenocarcinoma, breast, colon, and brain.